The present invention concerns a gene product largely homologous to the epithelial growth factor receptor (EGFR). It further refers to mRNA coding for such epithelial growth factor receptor. Further, the present invention concerns the use of such a gene product as tumor marker, particularly for epithelial tumors like colon cancer, lung cancer, prostate cancer, breast cancer or other solid tumors.
Histochemical studies of primary tumors often neglect the fact that in normal and tumor cells, different variants (also called derivatives or mutants) of therapy target genes, e.g. EGFR DNA rearrangement, EGFR transcription and/or protein variants exist. The growth factor receptor EGFR is of special importance in most epithelial tumors like colon cancer, lung cancer, prostate cancer or breast cancer, because expression in primary tumors correlates with a shorter survival time/rate. Therefore, an expression of EGFR is a prerequisite for EGFR based therapy (antibodies like Erbitux or receptor tyrosine kinase inhibitors like Iressa). But about 30% of patients do not respond to antibody therapies. The reason could be that a part of the N-terminal domain of die EGFR is deleted as has been described for the variant EGFRvIII. These variants e.g. naturally occurring through alternative splicing or in tumor cells through somatic mutation) exist in the whole EGFR sequence. Soluble proteins arise without cytosolic C-terminal ends as well as membrane anchored proteins without the N-terminal ligand-binding domain. Tumor-specific variants of EGFR have been described, for example, in Kuan et al., 2001 Endocr. Relat. Cancer 8, 83-96: “EGF mutant receptor vIII as a molecular target in cancer therapy”.
Variant vIII is the most abundant in different tumors such as breast or ovarian cancer but not all tumors express this variant (e.g. small cell lung carcinoma (SCLC)).
Another set of variants are short deletions (<10 amino acids) or single nucleotide mutations in the receptor tyrosine kinase domain of the EGFR that are expressed in tumor cells in non-small cell lung carcinoma (NSCLC) or neuroblastoma.
Today, two new classes of therapies exist: (1) antibodies that compete with the ligands of EGFR for example EGF or TGF-α and block the N-terminal binding domain of the receptor (Erbitux) and (2) small molecular weight receptor tyrosine kinase inhibitors (Iressa, Tarceva) that bind to the intracellular receptor tyrosine kinase domain and block the ATP binding site reversibly or irreversibly. Both therapies eliminate signal transduction of the wild-type EGFR.
But the clinical experience shows that not all patients (about 20%) respond to such therapies even if the primary tumor was tested positive for EGFR expression by IHC and/or amplification with FISH. On the other hand, patients, which were tested negative with immunohistochemical methods, sometimes respond to Erbitux therapy. One reason can be that not all patients express the wild-type EGFR but some of the EGFR variants.
Variants without the N-terminal binding domain (e.g. variant III) do not bind Pantimumab. EGFR variants without somatic mutations in the receptor tyrosine kinase domain need higher doses of, for example Iressa, to block the whole signal transduction of the EGFR. Thus, Iressa or Tarceva have a pronounced effect in NSCLC patients with single nucleotide mutations. Some new antibodies against different EGFR variants (e.g. EGFRvIII) are in preclinical studies.